3-(4-((4-morpholinomethyl-benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione for the treatment of systemic lupus erythematosus

ABSTRACT

Provided herein are methods of using compounds and compositions for treating, managing, and/or preventing systemic lupus erythematosus (SLE). Pharmaceutical compositions and dosing regimens for use in the methods are also provided herein.

This application is a divisional application of U.S. application Ser.No. 15/312,450, which is a national phase entry pursuant to 35 U.S.C. §371 of International Application No. PCT/US2015/031345, filed May 18,2015, which claims priority to U.S. Provisional Application Nos.62/000,428, filed May 19, 2014, and 62/053,626, filed Sep. 22, 2014, theentireties of which are incorporated herein by reference.

1. FIELD

Provided herein are methods of treating, preventing, and/or managingsystemic lupus erythematosus (SLE), or one or more symptoms thereof,using Compound I or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, tautomer or racemic mixtures thereof, including(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dione.Pharmaceutical compositions and dosing regimens for such treatment,prevention, and/or management are also provided herein.

2. BACKGROUND

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune diseaseof unknown etiology that has many clinical manifestations. Almost anyorgan can be involved, but the most common manifestations are cutaneous,musculoskeletal and renal. SLE typically affects young women ofchildbearing potential between the ages of 15 to 44. The prevalence ofSLE is 300,000 patients in the United States and 4 million patientsworldwide, with an annual incidence of 15,000 in the United Statesalone.

The pathogenesis of SLE likely involves an array of componentsassociated with both genetic and environmental factors. Diseasesusceptibility is influenced by genes related to immune response and themajor histocompatability complex class I and II genes. Additionalsusceptibilitystems from interactions between the hormonal environmentand the hypothalamo-pituitaryadrenalaxis. In addition, the developmentof SLE is associated with a defective immuneresponse which affectsapoptotic cell clearance and immune complexes. The loss ofimmunetolerance, excess T cell help, defective B cell suppression, andthe shifting of T helper 1 (Th1) toTh2 and Th17 immune responses leadsto B cell hyperactivity and the production of pathogenicantibodies.External factors such as chemicals, drugs, ultraviolet light, diet andviruses alsocontribute to the onset of disease.

As SLE is a waxing and waning disease, it is often controlled withNSAIDs or low potency immunosuppression drugs (antimalarials and lowdose corticosteroids) for milder symptomology (muscoskeletalmanifestation, cutaneous manifestation and serositis). More prolongedand potent use of corticosteroids, as well as non-biologic diseasemodifying anti-rheumatic drugs (DMARDs), are standard treatments whichare also available to treat those patients who exhibit major organinvolvement. In conjunction with standard therapy, biological DMARDtherapies exist to augment treatment for those patients with moreextensive disease. Belimumab, a monoclonal antibody and B-lymphocytestimulator-specific inhibitor, has recently been approved for use inconjunction with corticosteroids and other standard therapies forautoantibody-positive SLE. In addition, Rituximab, a B-cell depleter, isoften used off-label as rescue medication for patients unresponsive tostandard treatment. However, there still remains a need for prophylacticor therapeutic drugs that can be used to treat or prevent SLE.

3. SUMMARY

Provided herein are methods of treating, managing, ameliorating and/orpreventing systemic lupus erythematosus (SLE) comprising administering atherapeutically effective amount of a compound of formula I

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,tautomer or racemic mixtures thereof.

In one embodiment, the compound is3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is a pharmaceutically acceptable salt of3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindo1-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dionehydrochloride.

In one embodiment, the compound is(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione,having the following structure:

or a pharmaceutically acceptable salt, solvate, hydrate, or tautomerthereof.

In one embodiment, the compound is(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is a pharmaceutically acceptable salt of(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dionehydrochloride.

In one embodiment, the compound is(R)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione,having the following structure:

or a pharmaceutically acceptable salt, solvate, hydrate, or tautomerthereof.

In one embodiment, the compound is(R)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is a pharmaceutically acceptable salt of(R)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is(R)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dionehydrochloride.

In certain embodiments, one or more symptoms of SLE are treated,managed, and/or prevented.

Also provided herein are pharmaceutical compositions, single unit dosageforms, and kits suitable for use in treating, preventing, amelioratingand/or managing SLE, which comprise Compound I, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, tautomer or racemicmixtures thereof, optionally in combination with one or more othertherapeutic agents.

Also provided herein are methods for identifying a subject having SLEwho is likely to be responsive to a treatment with Compound I, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,tautomer or racemic mixture thereof

Also provided herein are methods for assessing the efficacy of CompoundI, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, tautomer or racemic mixture thereof, in treating,preventing or managing SLE.

4. BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic illustration of the overall clinical study designfor Compound 1A in Systemic Lupus Erythematosus

FIG. 2A, FIG. 2B, and FIG. 2C depict overexpression of CRBN, IKZF1 andIKZF3 mRNA in SLE peripheral blood mononuclear cells.

FIG. 3A, FIG. 3B, FIG. 3C, and FIG. 3D depict that Compound 1A reducedAiolos and Ikaros protein levels in whole blood leukocyte subsets.

FIG. 4A and FIG. 4B depict effects of B cell stimulation and Compound 1Aon Ikaros and Aiolos protein levels over time.

FIG. 5A and FIG. 5B depict that Compound 1A inhibited SLE autoantibodyproduction in vitro.

FIG. 6A depicts that Compound 1A reduces Aiolos expression in CD19+ Bcells in healthy volunteers.

FIG. 6B depictd that Compound 1A reduced Aiolos expression in CD3+ Tcells in healthy volunteers.

FIG. 7A depicts that Compound 1A reduces peripheral blood CD19+ B cellcounts in healthy volunteers.

FIG. 7B depicts the effect of Compound 1A on peripheral blood CD3+ Tcell counts in healthy volunteers.

FIG. 8A depicts that Compound 1A dose-dependently increased IL-2production in healthy volunteers.

FIG. 8B depicts that Compound 1A dose-dependently decreased ex vivoIL-10 production in healthy volunteers.

5. DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there is a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to alleviating or reducing the severityof a disease or a symptom associated with the disease or condition beingtreated. The term contemplates that a compound provided herein isadministered after the onset of a disease or a symptom associated withthe disease or condition being treated.

As used herein, “prevent”, “prevention” and other forms of the wordinclude the inhibition of onset or progression of a disease or disorderor a symptom of the particular disease or disorder. In some embodiments,subjects with familial history of cancer are candidates for preventiveregimens. Generally, in the context of cancer, the term “preventing”refers to administration of the drug prior to the onset of signs orsymptoms of the disease being treated.

As used herein, and unless otherwise indicated, the term “managing”encompasses preventing the recurrence of the particular disease ordisorder in a subject who had suffered from it, lengthening the time asubject who had suffered from the disease or disorder remains inremission, reducing mortality rates of the subjects, and/or maintaininga reduction in severity or avoidance of a symptom associated with thedisease or condition being managed.

As used herein, the term “subject” or “patient” means an animal,typically a mammal, including a human being.

As used herein, and unless otherwise specified, the terms“therapeutically effective amount” and “effective amount” of a compoundrefer to an amount sufficient to provide a therapeutic benefit in thetreatment, prevention and/or management of a disease, to delay orminimize one or more symptoms associated with the disease or disorder tobe treated. The terms “therapeutically effective amount” and “effectiveamount” can encompass an amount that improves overall therapy, reducesor avoids symptoms or causes of disease or disorder or enhances thetherapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise specified, the term“prophylactically effective amount” of a compound is an amountsufficient to prevent a disease or condition, or one or more symptomsassociated with the disease or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

As used herein and unless otherwise indicated, the term“pharmaceutically acceptable salt” includes, but is not limited to, asalt of an acidic group that can be present in the compounds providedherein. Under certain acidic conditions, the compound can form a widevariety of salts with various inorganic and organic acids. The acidsthat can be used to prepare pharmaceutically acceptable salts of suchbasic compounds are those that form salts comprising pharmacologicallyacceptable anions including, but not limited to, acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, bromide, iodide, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate,malate, maleate, mandelate, methanesulfonate (mesylate), methylsulfate,muscate, napsylate, nitrate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, succinate, sulfate, tannate,tartrate, teoclate, triethiodide, and pamoate.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound provided herein or a salt thereof, further including astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces. The hydrates can be crystalline ornon-crystalline.

As used herein and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto compound provided herein. The term “solvate” includes hydrates (e.g.,monohydrate, dihydrate, trihydrate, tetrahydrate, and the like). Thesolvates can be crystalline or non-crystalline.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein, and unless otherwise indicated, the term“stereomerically pure” or “enantiomerically pure” means that a compoundcomprises one stereoisomer and is substantially free of its counterstereoisomer or enantiomer. For example, a compound is stereomericallyor enantiomerically pure when the compound contains 80%, 90%, or 95% ormore of one stereoisomer and 20%, 10%, or 5% or less of the counterstereoisomer. In certain cases, a compound provided herein is consideredoptically active or stereomerically/enantiomerically pure (i.e.,substantially the R-form or substantially the S-form) with respect to achiral center when the compound is about 80% ee (enantiomeric excess) orgreater, preferably, equal to or greater than 90% ee with respect to aparticular chiral center, and more preferably 95% ee with respect to aparticular chiral center.

As used herein, and unless otherwise indicated, the term“stereomerically enriched” or “enantiomerically enriched” encompassesracemic mixtures as well as other mixtures of stereoisomers of compoundsprovided herein (e.g., R/S=30/70, 35/65, 40/60, 45/55, 55/45, 60/40,65/35 and 70/30).

The terms “co-administration” and “in combination with” include theadministration of two or more therapeutic agents (for example, CompoundI or a composition provided herein and another modulator of leukocyticactivity, including activity of B cells and/or T cells, monocytes,macrophages, and other lymphoid or myeloid-derived cell types or otheractive agent) either simultaneously, concurrently or sequentially withno specific time limits. In one embodiment, Compound I, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,tautomer or racemic mixtures thereof, and at least one other agent arepresent in the cell or in the subject's body at the same time or exerttheir biological or therapeutic effect at the same time. In oneembodiment, the therapeutic agent(s) are in the same composition or unitdosage form. In another embodiment, the therapeutic agent(s) are inseparate compositions or unit dosage forms.

5.1 Compound I

In certain embodiments, Compound I for use in the methods providedherein, including the combination therapy, and in compositions providedherein is a compound of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,tautomer or racemic mixtures thereof.

In one embodiment, the compound is(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione,having the following structure:

or a pharmaceutically acceptable salt, solvate, hydrate, or tautomerthereof.

In one embodiment, the compound is(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is a pharmaceutically acceptable salt of(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dionehydrochloride.

In one embodiment, the compound is(R)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione,having the following structure:

or a pharmaceutically acceptable salt, solvate, hydrate, or tautomerthereof.

In one embodiment, the compound is(R)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is a pharmaceutically acceptable salt of(R)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In one embodiment, the compound is selected from3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione,3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dionehydrochloride,(R)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dione,(R)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dionehydrochloride,(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dioneand (S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dionehydrochloride.

Compound I, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, tautomer or racemic mixtures thereof, can be prepared bymethods known to one of skill in the art, for example, according to theprocedure described in US Publication No. 2011/0196150, the entirety ofwhich is incorporated herein by reference.

An exemplary method for preparation is described in Example 1.

5.2 Methods of Treatment

In certain embodiments, provided herein are methods of treating,preventing, and/or managing systemic lupus erythematosus (SLE), or asymptom thereof, comprising administering a therapeutically orprophylactically effective amount of Compound I, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, tautomer or racemicmixtures thereof, to a patient having SLE. In one embodiment, providedherein are methods of treating, preventing, and/or managing SLE or asymptom thereof, comprising administering a therapeutically effectiveamount of(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dione,or a pharmaceutically acceptable salt or solvate thereof, to a patienthaving SLE.

In one embodiment, provided herein are methods of preventing SLE or asymptom thereof, comprising administering an effective amount ofCompound I, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, tautomer or racemic mixtures thereof, to a patient at riskof having SLE. In one embodiment, provided herein are methods ofpreventing SLE or a symptom thereof, comprising administering aneffective amount of(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dione,or a pharmaceutically acceptable salt or solvate thereof, to a patientat risk of having SLE.

The phrase “Systemic lupus erythematosus” is interchangeably used hereinwith SLE and lupus and refers to all manifestations of the disease asknown in the art (including remissions and flares). In SLE, abnormalhyperactivity of B lymphocytes and massive abnormal production ofimmunoglobulin gamma (IgG) auto-antibodies play a key role. Thispathological process results in sequestration and destruction ofIg-coated cells, fixation and cleaving of complement proteins, andrelease of chemotaxins, vasoactive peptides and destructive enzymes intotissues (Hahn BH. Systemic Lupus Erythematosus. In: Kasper D L,Braunwald E, Fauci A S, Hauser S L, Longo D L, Jameson, J L, editors.In: Harrison's Principles of Internal Medicine (16th edition). New York(US): McGraw-Hill; 2005. pp.1960-1967).

Symptoms of SLE vary from person to person, and may come and go. In mostpatients, the symptoms include joint pain and swelling. Frequentlyaffected joints are the fingers, hands, wrists, and knees. Some patientsdevelop arthritis. Other common symptoms include: chest pain when takinga deep breath, fatigue, fever with no other cause, general discomfort,uneasiness, or ill feeling (malaise), hair loss, mouth sores, swollenlymph nodes, sensitivity to sunlight, skin rash—a “butterfly” rash overthe cheeks and bridge of the nose affects about half of people with SLE,in some patients, the rash gets worse in sunlight, and the rash may alsobe widespread.

Other symptoms depend on what part of the body is affected, and mayinclude the following:

-   -   Brain and nervous system: headaches, numbness, tingling,        seizures, vision problems, personality changes,    -   Digestive tract: abdominal pain, nausea, and vomiting,    -   Heart: abnormal heart rhythms (arrhythmias),    -   Lung: coughing up blood and difficulty breathing, and    -   Skin: patchy skin color, fingers that change color when cold        (Raynaud's phenomenon).

In one embodiment, only skin symptoms are manifested in SLE, i.e.,discoid lupus.

In one embodiment, SLE is skin predominant SLE.

In one embodiment, provided herein are methods of treating moderate,severe, or very severe SLE. The term “severe SLE” as used herein refersto an SLE condition where the patient has one or more severe orlife-threatening symptoms (such as hemolytic anemia, extensive heart orlung involvement, kidney disease, or central nervous systeminvolvement).

Further provided herein are methods for achieving one or more clinicalendpoints associated with SLE comprising administering an effectiveamount of Compound I, or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, tautomer or racemic mixtures thereof, to apatient in need thereof.

Further provided herein are methods for increasing the overall survival,objective response rate, time to progression, progression-free survivaland/or time-to-treatment failure of a patient having SLE comprisingadministering an effective amount of Compound I, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, tautomer or racemicmixtures thereof, to the patient.

The dose of Compound I, or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, tautomer or racemic mixtures thereof, to beadministered to a patient is rather widely variable and can be subjectto the judgment of a health-care practitioner. Doses of Compound I, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,tautomer or racemic mixtures thereof, vary depending on factors such as:specific indication or symptoms to be treated, prevented, or managed;age and condition of a patient; and amount of second active agent used,if any. In general, Compound I, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof,can be administered one to four or more times a day in a dose of about0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient'sbody weight in a patient, but the above dosage may be properly varieddepending on the age, body weight and medical condition of the patientand the type of administration. In one embodiment, the dose is about0.01 mg/kg of a patient's body weight to about 5 mg/kg of a patient'sbody weight, about 0.05 mg/kg of a patient's body weight to about 1mg/kg of a patient's body weight, about 0.1 mg/kg of a patient's bodyweight to about 0.75 mg/kg of a patient's body weight or about 0.25mg/kg of a patient's body weight to about 0.5 mg/kg of a patient's bodyweight.

In one embodiment, one dose is given per day. In any given case, theamount of Compound I or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, tautomer or racemic mixtures thereof administeredwill depend on such factors as the solubility of the active component,the formulation used and the route of administration. In one embodiment,application of a topical concentration provides intracellular exposuresor concentrations of about 0.01-10 μM.

In certain embodiments, Compound I or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, tautomer or racemic mixturesthereof is used in an amount of from about 0.1 mg to about 1000 mg perday, and can be adjusted in a conventional fashion (e.g., the sameamount administered each day of the treatment, prevention or managementperiod), in cycles (e.g., one week on, one week off), or in an amountthat increases or decreases over the course of treatment, prevention, ormanagement. In other embodiments, the dose can be from about 1 mg toabout 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg toabout 200 mg, from about 10 mg to about 100 mg, from about 0.1 mg toabout 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about50 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20mg. In other embodiments, the dose can be from about 0.1 mg to about 100mg, from about 0.1 mg to about 50 mg, from about 0.1 mg to about 25 mg,from about 0.1 mg to about 20 mg, from about 0.1 mg to about 15 mg, fromabout 0.1 mg to about 10 mg, from about 0.1 mg to about 7.5 mg, fromabout 0.1 mg to about 5 mg, from about 0.1 mg to about 4 mg, from about0.1 mg to about 3 mg, from about 0.1 mg to about 2 mg, or from about 1mg to about 1 mg.

In some embodiments, Compound 1A, or a pharmaceutically acceptable saltor solvate thereof, is administered. In some embodiments, the dose ofCompound 1A, or a pharmaceutically acceptable salt or solvate thereof,is from about 0.15 mg to about 0.6 per day. In one embodiment, the doseof Compound 1A, or a pharmaceutically acceptable salt or solvatethereof, is 0.3 mg given every other day. In one embodiment, the dose ofCompound 1A, or a pharmaceutically acceptable salt or solvate thereof,is 0.3 mg given everyday. In one embodiment, the dose of Compound 1A, ora pharmaceutically acceptable salt or solvate thereof, is 0.6 mg and 0.3mg given on alternating days. In one embodiment, the dose of Compound1A, or a pharmaceutically acceptable salt or solvate thereof, is 0.6 mggiven everyday.

In some embodiment, patients are started on high dose treatment, and ifsignificant adverse effects persist, doses are adjusted, i.e., lowered,accordingly. For example, patients may start on a dose of 0.6 mg giveneveryday of Compound 1A, or a pharmaceutically acceptable salt orsolvate thereon, and if significant adverse effects persist, then mayadjust the dose in a step-wise fashion to 0.6 mg and 0.3 mg given onalternating days, then to 0.3 mg given everyday, and to 0.3 mg givenevery other day.

In some embodiments, administration of the compound continues for aperiod of from about 2 weeks to about 16 weeks. In one embodiment,administration of the compound continues for a period of about 28 days.In another embodiment, administration of the compound continues for aperiod of about 56 days. In yet another embodiment, administration ofthe compound continues for a period of about 84 days.

In some embodiments, the compound is administered orally. In oneembodiment, the compound is administered in a capsule. In oneembodiment, the capsule is in an amount of about 0.3 mg. In anotherembodiment, the compound is administered in a tablet.

In some embodiments, provided herein is a method for identifying asubject having systemic lupus erythematosus (SLE) who is likely to beresponsive to a treatment with Compound I, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, tautomer or racemicmixture thereof, comprising:

(a) determining the level of a biomarker in a first sample from thesubject, wherein the biomarker is selected from the group consisting ofCRBN, IKZF1 (Ikaros), and IKZF3 (Aiolos); and

(b) comparing the level of the biomarker in the first sample to areference level of the biomarker; wherein the subject is likely to beresponsive to the treatment if the level of the biomarker in the firstsample is higher than the reference level of the biomarker.

In one embodiment, the method further comprises administering to thesubject an effective amount of the compound.

In one embodiment, the reference is prepared by using a second sampleobtained from a healthy subject not having SLE; and wherein the secondsample is from the same source as the first sample.

In one embodiment, the biomarker is CRBN. In another embodiment, thebiomarker is IKZF1. In yet another embodiment, the biomarker is IKZF3.

In one embodiment, the level of only one of the biomarkers is measured.In another embodiment, the levels of two or more of the biomarkers aremonitored simultaneously.

In one embodiment, the first sample is peripheral blood mononuclearcells (PBMC). In another embodiment, the first sample is whole bloodleukocyte. In one embodiment, the whole blood leukocyte is CD19+ Bcells, CD3+ T cells, CD14+ monocytes, or granulocytes.

In one embodiment, the levels of one or more of the biomarkers aremeasured by determining the mRNA levels of the biomarkers. In anotherembodiment, the levels of one or more of the biomarkers are measured bydetermining the cDNA levels of the biomarkers. In yet anotherembodiment, the levels of one or more of the biomarkers are measured bydetermining the protein levels of the biomarkers.

In one embodiment, the compound is(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dione.In another embodiment, the compound is(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dionehydrochloride.

In some embodiments, provided herein is a method of assessing theefficacy of Compound I, or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, tautomer or racemic mixture thereof, in treating,preventing or managing systemic lupus erythematosus (SLE), comprising:

(a) administering the compound to a subject having SLE;

(b) obtaining a first sample from the subject;

(c) determining the level of a biomarker in the first sample; and

(d) comparing the level of the biomarker from step (c) to a referencelevel of the biomarker, wherein a change in the level as compared to thereference is indicative of the efficacy of the compound in treating SLE.

In one embodiment, the method further comprises adjusting the amount ofthe compound administered to the subject.

In one embodiment, the reference is prepared by using a second sampleobtained from a healthy subject not having SLE; and wherein the secondsample is from the same source as the first sample. In anotherembodiment, the reference is prepared by using a second sample obtainedfrom the subject before administration of the compound; and wherein thesecond sample is from the same source as the first sample.

In one embodiment, the biomarker is CRBN. In another embodiment, thebiomarker is IKZFz1. In yet another embodiment, the biomarker is IKZF3.In yet another embodiment, the biomarker is an SLE autoantibody. In oneembodiment, the SLE autoantibody is an anti-dsDNA autoantibody. Inanother embodiment, the SLE autoantibody is an anti-phospholipidautoantibody. In yet another embodiment, the biomarker is peripheralblood B cell count. In yet another embodiment, the biomarker isperipheral blood T cell count. In yet another embodiment, the biomarkeris IL-1β. In yet another embodiment, the biomarker is IL-2.

In one embodiment, a decrease in the level of the biomarker in the firstsample as compared to the reference is indicative of the efficacy of thecompound in treating SLE. In another embodiment, an increase in thelevel of the biomarker in the first sample as compared to the referenceis indicative of the efficacy of the compound in treating SLE.

In one embodiment, the level of only one of the biomarkers is measured.In another embodiment, the levels of two or more of the biomarkers aremonitored simultaneously.

In one embodiment, the first sample is peripheral blood mononuclearcells (PBMC). In another embodiment, the first sample is whole bloodleukocyte. In one embodiment, the whole blood leukocyte is CD19+ Bcells, CD3+ T cells, CD14+ monocytes, or granulocytes.

In one embodiment, the levels of one or more of the biomarkers aremeasured by determining the mRNA levels of the biomarkers. In anotherembodiment, the levels of one or more of the biomarkers are measured bydetermining the cDNA levels of the biomarkers. In yet anotherembodiment, the levels of one or more of the biomarkers are measured bydetermining the protein levels of the biomarkers.

In one embodiment, the compound is(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dione.In another embodiment, the compound is(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dionehydrochloride.

5.3 Combination Therapy

Compound I, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, tautomer or racemic mixtures thereof, can be combined withother pharmacologically active compounds (“second active agents”) inmethods and compositions provided herein. Certain combinations may worksynergistically in the treatment of SLE, and conditions and symptomsassociated with SLE. Compound I, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof,can also work to alleviate adverse effects associated with certainsecond active agents, and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

In another embodiment, the method of treatment provided herein comprisesthe administration of a second therapeutic agent, wherein the secondtherapeutic agent is an anti-inflammatory drug, e.g., a steroidalanti-inflammatory drug, or a non-steroidal anti-inflammatory drug(NSAID), acetaminophen, naproxen, ibuprofen, acetylsalicylic acid, andthe like. In a more specific embodiment in which an NSAID isadministered, a proton pump inhibitor (PPI), e.g., omeprazole may alsoadministered. In one embodiment, the antiinflammatory agent is acorticosteroid. In another embodiment, the antiinflammatory agent iscolchicine.

In another embodiment, the second therapeutic agent is animmunomodulatory compound or an immunosuppressant compound such asazathioprine (Imuran™, Azasan™), methotrexate (Rheumatrex™, Trexall™),penicillamine (Depen™, Cuprimine™), cyclophosphamide (Cytoxan™),mycophenalate (CellCept™, Myfortic™), bosentan (Tracleer®), prednisone(Deltasone™, Liquid Pred™), and a PDES inhibitor. In another embodiment,where the affected individual has digital ulcerations and pulmonaryhypertension, a vasodilator such as prostacyclin (iloprost) may beadministered.

In another embodiment, the second therapeutic agent is an HDACinhibitor, such as romidepsin, vorinostat, panobinostat, valproic acid,or belinostat; or a biological agent, such as an interleukin, animmunomodulatory monoclonal antibody, or bacillus Calmette-Guérin (BCG).

In another embodiment, the second therapeutic agent is an inhibitor ofActRII receptors or an activin-ActRII inhibitor. Inhibitors of ActRIIreceptors include ActRIIA inhibitors and ActRIIB inhibitors Inhibitorsof ActRII receptors can be polypeptides comprising activin-bindingdomains of ActRII. In certain embodiments, the activin-binding domaincomprising polypeptides are linked to an Fc portion of an antibody(i.e., a conjugate comprising an activin-binding domain comprisingpolypeptide of an ActRII receptor and an Fc portion of an antibody isgenerated). In certain embodiments, the activin-binding domain is linkedto an Fc portion of an antibody via a linker, e.g., a peptide linker.

Examples of non-antibody proteins selected for activin or ActRIIAbinding and methods for design and selection of the same are found inWO/2002/088171, WO/2006/055689, WO/2002/032925, WO/2005/037989, US2003/0133939, and US 2005/0238646, each of which is incorporated hereinby reference in its entirety.

In one embodiment, the inhibitor of ActRII receptors is ACE-11. Inanother embodiment, the inhibitor of ActRII receptors is ACE-536.

In another embodiment, the second therapeutic agent is an agent that isconventionally used to treat SLE. Examples of such agents include, butare not limited to, an NSAID, a corticosteroid, a non-biologic diseasemodifying anti-rheumatic drug (DMARD), and a biological DMARD therapy(e.g., belimumab and rituximab).

Any combination of the above therapeutic agents, suitable for treatmentof SLE or symptoms thereof, can be administered. Such therapeutic agentscan be administered in any combination with Compound I, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,tautomer or racemic mixtures thereof, at the same time or as a separatecourse of treatment.

5.4 Cycling Therapy

In certain embodiments, Compound I, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, tautomer or racemic mixturesthereof, is cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in one embodiment, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another embodiment encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another embodiment, a compound providedherein is administered for a greater number of cycles than wouldtypically cause dose-limiting toxicity in a patient to whom a secondactive ingredient is not also being administered.

In one embodiment, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.03 mg toabout 10 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 0.1 mg to about 8 mg, from about0.3 mg to about 6 mg, from about 1 mg to about 4 mg, or about 2 mg,followed by a rest.

In one embodiment, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another embodiment,the combination of a compound provided herein and a second activeingredient is administered by intravenous infusion over about 90 minutesevery cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

5.5 Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,racemate, clathrate, or prodrug thereof. Pharmaceutical compositions anddosage forms can further comprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are disclosed above.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 20^(th) ed., Mack Publishing,Easton Pa. (2000).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise the second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

5.5.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 20th ed., Mack Publishing, Easton Pa. (2000).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or nonaqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

5.5.2 Controlled Release Dosage Forms

Active ingredients such as the compounds provided herein can beadministered by controlled release means or by delivery devices that arewell known to those of ordinary skill in the art. Examples include, butare not limited to, those described in U.S. Pat. Nos.: 3,845,770;3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595;5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480;5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945;5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363;6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358;6,699,500 each of which is incorporated herein by reference. Such dosageforms can be used to provide slow or controlled release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, microspheres, or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled release formulations known to those ofordinary skill in the art, including those described herein, can bereadily selected for use with the active ingredients provided herein.Thus, the compositions provided encompass single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. Ideally, the use of an optimally designed controlledrelease preparation in medical treatment is characterized by a minimumof drug substance being employed to cure or control the condition in aminimum amount of time. Advantages of controlled release formulationsinclude extended activity of the drug, reduced dosage frequency, andincreased subject compliance. In addition, controlled releaseformulations can be used to affect the time of onset of action or othercharacteristics, such as blood levels of the drug, and can thus affectthe occurrence of side (e.g., adverse) effects.

Most controlled release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the drug may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump may be used(see, Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al.,Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)).In another embodiment, polymeric materials can be used. In yet anotherembodiment, a controlled release system can be placed in a subject at anappropriate site determined by a practitioner of skill, i.e., thusrequiring only a fraction of the systemic dose (see, e.g., Goodson,Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)).Other controlled release systems are discussed in the review by Langer(Science 249:1527-1533 (1990)). The active ingredient can be dispersedin a solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient in such parenteral compositions is highly dependent onthe specific nature thereof, as well as the needs of the subject.

5.5.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

5.5.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences,16^(th), 18^(th) and 20^(th) eds., Mack Publishing, Easton Pa. (1980,1990 and 2000); and Introduction to Pharmaceutical Dosage Forms, 4thed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16^(th), 18^(th) and 20^(th) eds., MackPublishing, Easton Pa. (1980, 1990 and 2000).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, hydrates, prodrugs, clathrates,or stereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

5.5.5 Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise additional active ingredients such asother anti-inflammatory, immunomodulatory or immunosuppressantcompounds, or a combination thereof. Examples of the additional activeingredients include, but are not limited to, those disclosed herein.

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

6. EXAMPLES

The following Examples are presented by way of illustration, notlimitation. In the examples, test compound refers to(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dione.

6.1 Example 1 Preparation of(S)-3-[4-(4-morphlin-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindo-2-yl]piperidine-2,6-dionehydrochloride

6.1.1 3-Hydroxy-2-methyl-benzoic acid methyl ester

3-Hydroxy-2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800mL) in a 2 L three neck round bottom flask equipped with condenser,thermometer and stirring bar followed by the addition of MeOH (250 ml).H₂SO₄ (10 mL, 180 mmol) was added to above solution. The reactionmixture was stirred at 62° C. for 17 hours. The solvent was removed invacuo. The residue (200 mL) was added to water (600 mL) slowly at roomtemperature and a white solid was formed. The suspension was stirred inan ice bath for 30 minutes and filtered. The solid was washed with water(5×250 mL) and dried to give 3-hydroxy-2-methyl-benzoic acid methylester as a white solid (100 g, 87% yield). The compound was used in thenext step without further purification: LCMS MH=167; ¹H NMR (DMSO-d₆) δ2.28 (s, 3H, CH₃), 3.80 (s, 3H, CH₃), 6.96-7.03 (m, 1H, Ar), 7.09 (t,J=7.8 Hz, 1H, Ar), 7.14-7.24 (m, 1H, Ar), 9.71 (s, 1H, OH).

6.1.2 3-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-benzoic acid methylester

To a 1 L three neck RB flask equipped with stirring bar and thermometer,were added DMF (300 mL), methyl 3-hydroxy-2-methylbenzoate (90 g, 542mmol) and imidazole (92 g, 1,354 mmol). TBDMS-Cl (90 g, 596 mmol) wasadded to the above solution in portions to control the internal tempbetween 15-19° C. over 20 minutes, and after addition, the internal tempdropped below 1° C. The ice bath was removed and the reaction mixturewas stirred at room temperature for 16 hours. The reaction mixture wasadded to ice water (500 mL), and the resulting solution was divided intotwo portions (700 mL×2). Each portion was extracted with EtOAc (700 mL).Each organic layer was washed with cold water (350 mL) and brine (350mL). Organic layers were combined and dried by MgSO₄. The combinedorganic layer was concentrated to give 3-(tert-butyl-dimethyl-silanyloxy)-2-methyl-benzoic acid methyl ester as alight brown oil (160 g, 100% crude yield). The compound was used in thenext step without further purification: LCMS MH=281; ¹H NMR (DMSO-d₆)δ-0.21 (s, 6H, CH₃, CH₃), 0.73-0.84 (m, 9H, CH₃, CH₃, CH₃), 2.10 (s, 3H,CH₃), 3.60 (s, 3H, CH₃), 6.82 (dd, 1H, Ar), 6.97 (t, J=7.9 Hz, 1H, Ar),7.13 (dd, J=1.1, 7.7 Hz, 1H, Ar).

6.1.3 2-Bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-benzoic acidmethyl ester

NBS (49.8 g, 280 mmol) was added to methyl 3-(tert-butyldimethylsilyloxy)-2-methylbenzoate (78.4 g, 280 mmol) in methyl acetate(500 mL) at room temperature to give an orange colored suspension. Theresulting reaction mixture was heated in an oil bath at 40° C. andshined by 300 wt sunlight bulb at reflux for 4 hours. The reactionmixture was cooled down and washed by Na₂SO₃ solution (2×600 mL, 50%saturated concentration), water (500 mL) and brine (600 mL). The organiclayer was dried by MgSO₄ and decolorized by charcoal. The organic layerwas concentrated to give 2-bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-benzoic acid methyl ester as a light brownoil (96 g, 91% crude yield). The compound was used in the next stepwithout further purification: LCMS M-Br=279; ¹H NMR (DMSO-d₆) δ0.05-0.11 (m, 6H, CH₃, CH₃), 0.82 (s, 9H, CH₃, CH₃, CH₃), 3.65 (s, 3H,CH₃), 4.74 (s, 2H, CH₂), 6.94 (dd, J=1.3, 8.1 Hz, 1H, Ar), 7.10-7.20 (m,1H, Ar), 7.21-7.29 (m, 1H, Ar).

6.1.4 4-Carbamoyl-butyric acid methyl ester

To a stirred solution of methyl 2-(bromomethyl)-3-(tert-butyldimethylsilyloxy)benzoate (137.5 g, 325 mmol) in acetonitrile(1100 mL) in a 2 L round bottom flask, was added methyl4,5-diamino-5-oxopentanoate hydrochloride (70.4 g, 358 mmol). To thesuspension was added DIPEA (119 ml, 683 mmol) through an addition funnelover 10 minutes and the suspension was stirred at room temperature for 1hour before the mixture was heated in an oil bath at 40° C. for 23hours. The reaction mixture was concentrated under vacuo. The residuewas stirred in ether (600 mL), and a white solid precipitated out. Themixture was filtered and the solid was washed with ether (400 mL). Thefiltrate was washed with HCl (1N, 200 mL), NaHCO₃ (sat. 200 mL) andbrine (250 mL). The aqueous acid layer and basic layer were keptseparately. Then the solid was further washed with ether (250 mL) andthe liquid was washed with above acid solution and basic solution. Thetwo organic layers were combined and concentrated under vacuo to give4-[4-(tert-Butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a brown oil (152 g, 115% crude yield, 77% purity byH NMR). The compound was used in the next step without furtherpurification: LCMS MH=407.

6.1.5 4-Carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester

To a stirred cold solution of methyl5-amino-4-(4-(tert-butyldimethylsilyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(152 g, 288 mmol) in DMF (500 mL) and water (55 mL), was added by K₂CO₃(19.89 g, 144 mmol) by portions over 5 minutes. The resulting reactionmixture was stirred at room temperature for 40 minutes. The reactionmixture was cooled in an ice bath. To the mixture, HCl (12M, 23.99 ml,288 mmol) was added slowly. After the addition, acetonitrile (280 mL)was added to the mixture and a solid precipitated out. The mixture wasstirred at room temperature for 10 minutes and filtered. The solid waswashed with acetonitrile (50 mL×4). The filtrate was concentrated underhigh vacuo to give a yellow oil (168 g). The oil was dissolved inacetonitrile (600 mL) and stirred at room temperature for 10 minutes.The mixture was filtered and the solid was washed with acetonitrile (25mL×2). The filtrate was concentrated under high vacuo to give a yellowoil (169 g), which was added to a mixture of water (1200 mL) and ether(1000 mL). The mixture was stirred for 3 minutes and the layers wereseparated. The aqueous solution was concentrated under high vacuo andthe residue was stirred in acetonitrile (160 mL) and a white solid wasformed after overnight stirring. The mixture was filtered to give4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester as a white solid (46 g, 54% yield). The filtrate wasconcentrated and the residue was further crystallized in acetonitrile(60 mL) to give more4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester as a white solid(11.7 g, 14% yield). The filtrate wasconcentrated and the residue was purified by ISCO chromatography to givemore 4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol -2-yl)-butyricacid methyl ester as a white solid (13.2 g, 15% yield). The totalproduct obtained was 70.9 g in 83% yield: LCMS MH=293; ¹H NMR (DMSO-d₆)δ 1.95-2.34 (m, 4H, CH₂, CH₂), 3.51 (s, 3H, CH₃), 4.32 (d, J=17.6 Hz,1H, CHH), 4.49 (d, J=17.4 Hz, 1H, CHH), 4.73 (dd, J=4.7, 10.2 Hz, 1H,CHH), 6.99 (dd, J=0.8, 7.9 Hz, 1H, Ar), 7.10-7.23 (m, 2H, Ar, NHH),7.25-7.38 (m, 1H, Ar), 7.58 (s, 1H, NHH), 10.04 (s, 1H, OH).

6.1.63-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Step 1: To the solution of3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (2.5g, 8.56 mmol) in THF (60 mL) was added triphenyl phosphine (polymersupported 1.6 mmol/g, 12 g, 18.8 mmol). The mixture was stirred at roomtemperature for 15 minutes. Diisopropyl azodicarboxylate (3.96 mL, 18.8mmol) was added at 0° C., and the mixture was stirred at 0° C. for 30minutes. (4-Morpholin-4-ylmethyl-phenyl)-methanol (2.62 g,12.4 mmol) wasadded at 0° C., and the mixture was allowed to warm to room temperatureand stirred at room temperature overnight. The reaction mixture wasfiltered, and the filtrate was concentrated. The resulting oil waspurified on silica gel column eluted with methylene chloride andmethanol (gradient, product came out at 6% methanol) to give4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (2.2 g, 54% yield). The product was used in the nextstep without further purification.

Step 2: To the THF solution (50 mL) of4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (2.2 g, 4.57 mmol) was added potassium tert-butoxide(0.51 g, 4.57 mmol) at 0° C. The mixture was stirred at 0° C. for 10minutes and was quenched with 1N HCl (5 mL, 5mmol) followed by saturatedNaHCO₃ (25 mL). The mixture was extracted with EtOAc (2×50 mL). Theorganic layer was washed with water (30 mL), brine (30 mL), dried overMgSO₄ and concentrated. To the resulting solid was added EtOAc (10 mL)followed by hexane (10 mL) under stirring. The suspension was filteredto give3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas white solid (1.5 g, 73% yield). HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, gradient to 95/5 acetonitrile/0.1% H₃PO₄in 5 min,: t_(R)=4.78 min (97.5%); mp: 210-212° C.; ¹H NMR (DMSO-d₆) δ1.86-2.09 (m, 1H, CHH), 2.29-2.38 (m, 4H, CH₂,CH₂), 2.44 (dd, J=4.3,13.0 Hz, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.82-2.99 (m, 1H, CHH), 3.46(s, 2H, CH₂), 3.52-3.61 (m, 4H, CH₂,CH₂), 4.18-4.51 (m, 2H, CH₂), 5.11(dd, J=5.0, 13.3 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.27-7.38 (m, 5H, Ar),7.40-7.53 (m, 3H, Ar), 10.98 (s, 1H, NH) ¹³C NMR (DMSO-d₆) δ 22.36,31.21, 45.09, 51.58, 53.14, 62.10, 66.17, 69.41, 114.97, 115.23, 127.64,128.99, 129.81, 129.95, 133.31, 135.29, 137.68, 153.50, 168.01, 170.98,172.83; LCMS: 465; Anal Calcd for C₂₅H₂₇N₃O₅+0.86 H₂O: C, 64.58; H,6.23; N, 9.04; Found: C, 64.77; H, 6.24; N, 8.88.

(S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneand(R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionewere prepared from3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionethrough chiral separation.

6.2 Example 2 Clinical Studies—SLE

6.2.1 Study Design

A phase 2, randomized, placebo-controlled, double-blind, pilot,multicenter study is conducted to evaluate the preliminary efficacy,safety, tolerability, pharmacokinetics, pharmacodynamics andpharmacogenetics of Compound 1 in subjects with SLE. This study isconducted in two parts.

Part 1

Part 1 is a randomized, double-blind, placebo-controlled, ascending dosestudy to evaluate the safety and tolerability of Compound 1A in SLEsubjects. Subject participation in Part 1 will consist of 3 phases:

-   -   Pre-treatment Screening Phase: up to 28 days prior to the first        dose of the investigational product (IP)    -   Treatment Phase: Up to 84 days    -   Observation Phase: 84 day post-treatment

A total of approximately 40 subjects will be randomized into 4 dosegroups with a 4:1 ratio of Compound 1A (0.3 mg every other day [QOD],0.3 mg everyday [QD], 0.6 mg and 0.3 mg on alternating days and 0.6 mgQD) or matching placebo (8 subjects in the IP arm and 2 subjects in theplacebo arm for each dose group) using an Interactive Voice ResponseSystem (IVRS). Subjects will be randomized into the first two dosegroups of 0.3 mg QOD and 0.3 mg QD in parallel. Following confirmationof safety of the first two dose groups, remaining subjects will then berandomized into the 0.6 mg and 0.3 mg on alternating days and 0.6 mg QDdose groups in a sequential, dose-ascending manner (first the 0.6 mg and0.3 mg on alternating days dose group followed by the 0.6 mg QD dosegroup). The treatment phase will be up to 84 days in duration for alldose groups. Subjects who discontinue IP early will enter into theobservational follow-up phase for an 84 day period. In all cases ofEarly Termination from the study, subjects will be encouraged tocomplete an Early Termination Visit. A graphical representation of Part1 dosing administration schedule is shown in FIG. 1.

All subjects will be allowed to remain on stable doses ofhydroxychloroquine, chloroquine, and/or quinacrine during the course ofthe study, provided subjects are on one of these antimalarials for ≥16weeks prior to their baseline visit and maintain a stable dose for atleast 4 weeks prior to dosing and throughout the study. No additionalsystemic immunosuppressives will be permitted. In addition, as needed(PRN) treatment with systemic anti-pruritics and/or systemic analgesicswill be permitted, however, subjects must stop using all systemicanti-pruritics 48 hours prior to all study visits and systemicanalgesics 12 hours prior to all study visits. Oral non-steroidalanti-inflammatory drugs (NSAIDs) may be used PRN, but must be stopped 12hours prior to all study visits. Use of oral corticosteroids will bepermitted only at doses of 10 mg or less per day and must be maintainedat a stable dose during study participation. No IV corticosteroids willbe permitted during the study. No other, local or systemic treatmentsfor dermatological manifestations of lupus will be permitted.

Following completion of the first 28 days of the treatment phase by atleast 8 subjects in Dose Group 1 (0.3 mg QOD) and Dose Group 2 (0.3 QD),an assessment of safety and tolerability will be conducted. If DoseGroup 1 and 2 are deemed safe, subjects will continue to receive studymedication for up to 84 days and enrollment of subjects into Dose Group3 (0.6 mg and 0.3 mg on alternating days) will be initiated. Followingcompletion of the first 28 days of the treatment phase by at least 8subjects in Dose Group 3 (0.6 mg and 0.3 mg on alternating days), anassessment of safety and tolerability will be conducted. If Dose Group 3is deemed safe, subjects will continue to receive study medication forup to 84 days and enrollment of subjects into Dose Group 4 (0.6 mg QD)will be initiated. Following completion of the first 28 days of thetreatment phase by at least 8 subjects in Dose Group 4 (0.6 mg QD), anassessment of safety and tolerability will be conducted. If Dose Group 4is deemed acceptable, subjects will continue to receive study medicationfor up to 84 days.

Subjects will remain on their assigned treatment for up to 84 days. Inthe event a subject experiences clinically significant IP-relatedadverse events (AEs), a dose interruption for up to 14 days will bepermitted. If a subject is unable to remain on their assigned dose,he/she will reduce their dose to the next lowest dosing regimen. Dosereductions will occur as follows:

-   -   Subjects on 0.6 mg QD will reduce their dose to 0.6 mg/0.3 mg on        alternating days    -   Subjects on 0.6 mg/0.3 mg on alternating days will reduce their        dose to 0.3 mg QD    -   Subjects on 0.3 mg QD will reduce their dose to 0.3 mg QOD    -   Subjects on 0.3 mg QOD will reduce their dose to placebo

A subject will only be permitted to reduce their dose one time duringthe study. The decision to modify IP dosing will be based on theInvestigator's clinical judgment. The sponsor should be notified of theintent to dose reduce prior to a change in dosing. Subjects whodiscontinue from the study prior to completing 28 days of treatment maybe replaced (for up to a total of 10 subjects for Part 1) at thediscretion of the sponsor.

Subjects who participate in Part 1 of the study will not be permitted toparticipate in Part 2 of the study.

Part 2

Part 2 is a randomized, placebo-controlled, double-blind, parallel groupstudy to evaluate the efficacy and safety of Compound 1A in skinpredominant SLE subjects. Part 2 will only be initiated once up to 8subjects have completed 28 days of treatment in the 0.6 mg QD dose groupfor Part 1 and the 28 day safety assessment of the 0.6 mg QD dose groupin Part 1 is completed.

Subject participation in Part 2 will consist of 3 phases:

-   -   Pre-treatment Screening Phase: up to 28 days prior to the start        of the IP    -   Treatment Phase: Up to 84 days    -   Observation Phase: 84 day post-treatment

Up to a total of approximately 100 subjects will be randomized into 4dose groups of Compound 1A (0.3 mg QOD, 0.3 mg QD, 0.6 mg and 0.3 mg onalternating days and 0.6 mg QD) or matching placebo (20 subjects in eachCompound 1A dosing arm and 20 subjects in the placebo arm) using anIVRS. The dose groups included in Part 2 will be dependent on resultsfrom Part 1. Any dose group which does not demonstrate adequate safety,tolerability or PD may not be used in Part 2. The treatment phase forPart 2 will be up to 84 days in duration. Subjects who discontinue IPearly will enter into the observational follow-up phase for a 84 dayperiod. In all cases of early termination from the study, subjects willbe encouraged to complete an Early Termination Visit.

All subjects will be allowed to remain on stable doses ofhydroxychloroquine, chloroquine, and/or quinacrine during the course ofthe study, provided subjects are on one of these antimalarials for ≥16weeks prior to their baseline visit and maintain a stable dose for atleast 4 weeks prior to dosing and throughout the study. No additionalsystemic immunosuppressives will be permitted. In addition, PRNtreatment with systemic anti-pruritics and/or systemic analgesics willbe permitted. However, subjects must stop using all systemicanti-pruritics 48 hours prior to all study visits and systemicanalgesics 12 hours prior to all study visits. Oral NSAIDs may be usedPRN, but must be stopped 12 hours prior to all study visits. Use of oralcorticosteroids will be permitted only at doses of 10 mg or less per dayand must be maintained at a stable dose during study participation. NoIV corticosteroids will be permitted during the study. No other topical,local or systemic treatments for dermatological manifestations of SLEwill be permitted.

Subjects will remain on their assigned treatment for up to 84 days. Inthe event a subject experiences clinically significant IP-related AEs, adose interruption for up to 14 days will be permitted. If a subject isunable to remain on their assigned dose, he/she will reduce their doseto the next lowest dosing regimen. Dose reductions will occur asfollows:

-   -   Subjects on 0.6 mg QD will reduce their dose to 0.6 mg/0.3 mg on        alternating days    -   Subjects on 0.6 mg/0.3 mg on alternating days will reduce their        dose to 0.3 mg QD    -   Subjects on 0.3 mg QD will reduce their dose to 0.3 mg QOD    -   Subjects on 0.3 mg QOD will reduce their dose to placebo

A subject will only be permitted to reduce their dose one time duringthe study. The decision to modify IP dosing will be based on theInvestigator's clinical judgment. The sponsor should be notified of theintent to dose reduce prior a change in dosing.

Subjects who discontinue from the study prior to completing 28 days oftreatment may be replaced (for up to a total of 10 subjects in Part 2)at the discretion of the sponsor.

For both Part 1 and Part 2, subjects will have regularly scheduledvisits to assess IP activity and safety. Required assessments will becompleted as depicted in Tables 1 and 2.

TABLE 1 Part 1 Pre- treatment Observational Phase Treatment PhaseFollow-Up Phase Visit(s) ±1 Day - Days −28 to 29 ±2 Days - Days 43 to169 10 Final Treatment Visit/Early 1 2 Termination Screening Baseline 34 5 6 7-9 Visit 11 12 13 14 Day(s) Day 99 Day 113 Day 141 Day 1692-weeks 4-weeks 8-weeks 12-weeks Post- Post- Post- Post- −28 1 8 15 2229 43, 57, 71 85 treatment treatment treatment treatment Study EntryInformed Consent X — — — — — — — — — — — Inclusion/Exclusion Criteria XX — — — — — — — — — — Medical History X — — — — — — — — — — —Ophthalmology Exams X — — — — — — X — — — — Safety Assessments CompletePhysical Exam X — — — — — — X — X — X Targeted Physical Exam — X — — X —Day 57 — X — — — Vital Signs X X X X X X X X X X X X Hepatitis B & CScreening X — — — — — — — — — — — Serum Hematology, Chemistry X X — X —X X X — X X X and Urinalysis IgA, IgG and IgM — X — — — — Day 57 X — X —— Inflammation Panel — X X X — X Day 57 X — X — — Serum β-HCG PregnancyTest^(a) X X — — — X Day 57 X — X — — Urine Pregnancy Test^(b) — X X X XX X — — — — — Tetanus toxoid, meningococcal/, — X — — — — — X — — — —pneumococcal and influenza titer Administration of tetanus toxoid, — — X— — — — — — — — — meningococcal, pneumococcal and/or influenza vaccinesApolipoproteins, total — X — — — X Day 57 X — X — — cholesterol andlipid-soluble vitamins A, D, E and K PT, INR and PTT — X — — — — Day 43X — X — X 12-Lead ECG X X X — — — Day 43 X X — — — Adverse Events X X XX X X X X X X X X Concomitant Meds and X X X X X X X X X X X XProcedures Celgene Pregnancy Prevention X X — X — X X X X — — —Counseling Program (CPPCP) Efficacy Assessments CLASI Activity X X X X —X Day 57 X — X — — CLASI Damage — X — — — — Day 57 X — — — — HybridSELENA SLEDAI X X X X — X Day 57 X — X — — Swollen and Tender JointCount — X X X — X Day 57 X — X — — PGA — X X X — X Day 57 X — X — —Pericarditis/Pleuritic Pain Scale X X X X — X Day 57 X — X — — HAQ-DI —X X X — X Day 57 X — X — — SF-12 — X — — — X Day 57 X — — X — DLQI — X —— — — — X — — X — EQ-5D — X — — — — — X — — — X FACIT-F — X — X — X Day57 X — X — — LupusPRO — X — — — — Day 57 X — X — — PK/PD AssessmentsSparse PK Blood Collection — — — X — X Day 57 X — — — — Intensive PKBlood Collection — X — X — X Day 57 X — — — — Peripheral Blood Sample —X — — — X Day 57 X — — — — Collection for Lymphocyte Subset Analyses SLEbiomarker flow cytometry — X — — — X Day 57 X — — — — (aiolos andikaros) Lupus Autoantibody/ X X X — — X Day 57 X X X X X ComplementPanel Lupus Anti-Phospholipid Profile — X — — — — — X X — — —Investigational Product Dispense IP — X X — X X — — — — — IP Compliance— — X X X X X X — — — — ^(a)FCBP are required to have 2 negativepregnancy tests (sensitivity of at least 25 mIU/mL) prior to startingIP. The first pregnancy test must be performed within 10 to 14 daysprior to the start of IP and the second test must be performed within 24hours of starting IP. The subject may not receive IP until theInvestigator has verified that the results of these pregnancy tests arenegative. FCBP with regular or no menstrual cycles must have pregnancytesting weekly for the first 4 weeks of study participation and thenevery 28 days while on study, at study discontinuation and at Day 28following study discontinuation. If menstrual cycles are irregular, thepregnancy testing must occur weekly for the first 28 days and then every14 days while on study, at study discontinuation and at Days 99 and 113following study discontinuation. ^(b)All male the FCBP subjects must becounseled about pregnancy precautions and risks of fetal exposure. Allsubjects must also be counseled against sharing investigational productand donating blood during and within 28 days of discontinuinginvestigational product.

TABLE 2 Part 2 Pre- treatment Phase Treatment Phase ObservationalFollow-Up Phase Visit(s) ±1 Day - Days −28 to 29 ±2 Days - Days 43 to169 10 Final Treatment Visit/Early 1 2 Termination Screening Baseline 34 5 6 7-9 Visit 11 12 13 14 Day(s) Day 99 Day 113 Day 141 Day 1692-weeks 4-weeks 8-weeks 12-weeks Post- Post- Post- Post- −28 1 8 15 2229 43, 57, 71 85 treatment treatment treatment treatment Study EntryInformed Consent X — — — — — — — — — — — Inclusion/Exclusion Criteria XX — — — — — — — — — — Medical History X — — — — — — — — — — —Ophthalmology Exams X — — — — — — X — — — — Safety Assessments CompletePhysical Exam X — — — — — — X — X — X Targeted Physical Exam — X — — X —Day 57 — X — — — Vital Signs X X X X — X X X X X X X Hepatitis B & CScreening X — — — — — — — — — — — Serum Hematology, Chemistry X X — X —X X X — X X X and Urinalysis IgA, IgG and IgM — X — — — — Day 57 X — X —— Inflammation Panel — X X X — X Day 57 X — X — — Serum β-HCG PregnancyTest^(a) X X — — — X Day 57 X — X — — Urine Pregnancy Test^(b) — X X X XX X — — — — — Tetanus Toxoid, meningococcal, — X — — — — — X — — — —pneumococcal and influenza titer Administration of tetanus toxoid, — — X— — — — — — — — — meningococcal/pneumococcal and/or influenza vaccinesApolipoproteins, total — X — — — X Day 57 X — X — — cholesterol andlipid-soluble vitamins A, D, E and K PT, INR and PTT — X — — — — Day 43X — X — X 12-Lead ECG X X X — — — Day 43 X X — — — Adverse Events X X XX X X X X X X X X Concomitant Meds and X X X X X X X X X X X XProcedures Celgene Pregnancy Prevention X X — X — X X X X — — —Counseling Program (CPPCP) Efficacy Assessments CLASI Activity X X X X —X Day 57 X — X — — CLASI Damage — X — — — — Day 57 X — — — — HybridSELENA SLEDAI X X X X — X Day 57 X — X — — PGA — X X X — X Day 57 X — X— — Swollen and Tender Joint Count — X X X — X Day 57 X — X — —Pericarditis/Pleuritic Pain Scale X X X X — X Day 57 X — X — — HAQ-DI —X X X — X Day 57 X — X — — SF-12 — X — — — X Day 57 X — — X — DLQI — X —— — — — X — — X — EQ-5D — X — — — — — X — — — X FACTT-F — X — X — X Day57 X — X — — LupusPRO — X — — — — Day 57 X — X — — PK/PD AssessmentsSparse PK Blood Collection — — — X — X Day 57 X — — — — Intensive PKBlood Collection — X — X — X — — — — — — Peripheral Blood Sample — X — —— X Day 57 X — — — — Collection for Lymphocyte Subjet Analyses SLEbiomarker flow cytometry — X — — — — — — — — — — (aiolos and ikaros)Lupus Autoantibody/ X X X — — X Day 57 X X X X X Complement Panel LupusAnti-Phospholipid Profile — X — — — — — X X — — — Pharmacogenetic Blood— X — — — — — — — — — — Collection Dispense IP — X — X — X X — — — — —IP Compliance — — X X X X X X — — — — ^(a)FCBP are required to have 2negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior tostarting IP. The first pregnancy test must be performed within 10 to 14day prior to the start of IP and the second test must be performedwithin 24 hours of starting IP. The subject may not receive IP until theInvestigator has verified that the results of these pregnancy tests arenegative. FCBP with regular or no menstrual cycles must have pregnancytesting weekly for the first 4 weeks of study participation and thenevery 28 days while on study, at study discontiunation and at Day 28following study discontiunation. If menstrual cycles are irregular, thepregnancy testing must occur weekly for the first 28 days and then every14 days while on study, at study discontiunation and at Days 99 and 113following study discontiunation. ^(b)All male and FCBP subjects must becounseled about pregnancy precautions and risks of fetal exposure. Allsubjects must also be counseled against sharing investigational productand donating blood during and within 28 days of discontinuinginvestigational product

Upon completion of, or discontinuation from the Treatment Phase for Part1 or Part 2, all subjects (including premature discontinuations) will befollowed bi-weekly for the first 28 days and then monthly for theremaining 56 days in a 28 day Observational Follow-up Phase. This studywill be conducted in compliance with the protocol, good clinicalpractice (GCP) and applicable regulatory requirements.

6.2.2. Study Population

The study population consists of male and female subjects 18 years ofage and older at the time of signing the ICD for both Part 1 and Part 2.

Subjects in Part 1 are required to have an established diagnosis of SLEas defined by the 1997 Update of the 1982 American College ofRheumatology (ACR) Revised Criteria for Classification of SLE atScreening.

Subjects in Part 2 are required to have:

-   -   An established diagnosis of SLE as defined by the 1997 Update of        the 1982 ACR Revised Criteria for Classification of SLE at        Screening    -   A clinical diagnosis of SLE with dermatologic manifestations of        lupus disease for at least 16 weeks prior to screening, and        consistent findings on skin biopsy based on Gilliam        classification    -   Active skin lesions of sufficient severity, based on the        Cutaneous Lupus Area and Severity Index (CLASI) (CLASI Activity        Score ≥10) at Baseline    -   Active SLE arthritis defined as at least 3 tender joints at        Baseline    -   Positive antibodies associated with SLE, which must include one        of the following:        -   Anti-nuclear Antibodies (ANA) defined as a titer of 1:160 or            greater via Immunoflourescence Assay (IFA) within the            Screening period        -   Positive ds-DNA antibodies defined as ≥30 IU within the            Screening period        -   Anti-nuclear antibodies (SS-A [Ro], SS-B(La), Smith or RNP)            within the

Screening period

6.2.3 Length of Study

The length of study participation for each subject is 196 days (Up to a28 day Screening Phase, 84 day Treatment Phase and a 84 dayObservational Follow-Up Phase) for both Part land Part 2 participants.

The End of Trial is defined as either the date of the last visit of thelast subject to complete the study, or the date of receipt of the lastdata point from the last subject that is required for primary, secondaryand/or exploratory analyses, as pre-specified in the protocol and/or theStatistical Analysis Plan, whichever is the later date.

6.2.4. Study Treatment

Compound 1A will be provided as 0.3 mg capsules. Standard matchingplacebo capsules will also be provided. Capsules will be taken by mouth(PO) with or without food.

Subjects will be randomized to one of the 4 following dose groups forPart 1. If all four dose groups demonstrate sufficient safety,tolerability and/or efficacy during Part 1, the same four dose groupswill be used for Part 2. Investigational product will be administered POas described below:

Compound 1A

-   -   0.3 mg QOD        -   Subjects will receive 0.3 mg once every other day    -   0.3 mg QD        -   Subjects will receive 0.3 mg every day    -   0.6 mg and 0.3 mg on alternating days        -   Subjects will receive 0.6 mg and 0.3 mg on alternating days.    -   0.6 mg QD        -   Subjects will receive 0.6 mg every day

Placebo

Subjects assigned to the placebo group will receive matching placebocapsule(s) daily. In the event a subject on placebo experiencesclinically significant IP-related AEs, a dose interruption for up to 14days will be permitted. If a subject is unable to remain on theirplacebo, the subject may discontinue IP early and enter into either an84 day observational follow-up phase for Part 1 or a 28 day follow-upphase for Part 2. In all cases of early termination from the study,subjects will be encouraged to complete an Early Termination Visit. Thedecision to modify IP dosing will be based on the Investigator'sclinical judgment. The sponsor should be notified of the intent to dosereduce prior a change in dosing. In the event that a subject experiencesa flare during the observational follow-up period, the PI may treat thesubject with the standard of care in order to allow the subject toremain in the study and continue with the scheduled visits andassessments indicated by the schedule of assessments.

6.2.5 Overview of Safety Assessments

Safety is assessed based on the following criteria:

-   -   Adverse events    -   Vital signs, including height, weight, pulse, temperature and        blood pressure    -   Hematology, serum chemistry, urinalysis    -   Inflammation panel    -   Serum beta-human chorionic gonadotropin (HCG) and urine        pregnancy tests (for females of childbearing potential [FCBP])    -   Tetanus toxoid, meningococcal, pneumococcal and influenza        vaccine titers    -   Centralized 12-lead electrocardiograms (ECGs)    -   Physical examinations, including height and weight    -   Concomitant medications and procedures    -   Ophthalmological exams    -   Hepatitis screening

6.2.6 Overview of Pharmacokinetic Assessments

Blood samples for quantification of Compound 1A in plasma will be takenat specified time points (Tables 1 and 2) during the course of thestudy. A minimum of 4 subjects in each of the 4 treatment groups in Part1 and Part 2 (minimum total of 32 subjects) will be targeted forparticipation in the intensive PK portion of the study. The IVRS will beused to ensure inclusion of a minimum of 4 intensive PK participants perdose group. Noncompartmental PK parameters of ompound 1A will beestimated from these subjects. All other subjects who do not participatein the intensive PK portion of the study will have sparse PK samplescollected.

6.2.7 Overview of Pharmacodynamic Assessments

Pharmacodynamic profile is assessed based on the following:

-   -   The PD markers aiolos and ikaros will be measured in peripheral        white blood cells in Part 1 and Part 2    -   Peripheral blood lymphocyte subsets will be measured will be        measured in Part 1 and Part 2    -   Lupus Autoantibody/Complement Panel (anti-Ro, anti-La        anti-dsDNA, anti-smith, rheumatoid factor, anti-RNP, C3, C4,        cell-bound complement activated products (CB-CAPs), CH50, ANA,        ANCA, anti-thyroid antibodies) in Part 1 and Part 2

6.2.8 Overview of Efficacy Assessments

Efficacy is assessed based on the following:

-   -   Cutaneous Lupus Area and Severity Index (CLASI)    -   Hybrid SELENA Systemic Lupus Erythematosus Disease Activity        Index (SLEDAI)    -   Physician's Global Assessment (PGA)    -   Swollen and Tender Joint Counts    -   Pericardial/Pleuritic Pain Numerical Rating Scale

6.2.9 Overview of Quality-of-Life Assessments

Overall quality of life is assessed based on the following:

-   -   Functional Assessment of Chronic Illness Therapy—Fatigue        (FACIT-F)    -   Short form—12 (SF-12)    -   EQ-5D    -   Dermatology Life Quality Index (DLQI)    -   Disability Index of the Health Assessment Questionnaire (HAQ-DI)    -   Lupus Patient Reported Outcome Tool (LupusPRO)

6.2.10 Overview of Pharmacogenetic Assessments

Pharmacogenetic profile can be assessed using Single NucleotidePolymorphisms in genes associated with SLE, such as, but not limited toIKZF1 and IKZF3.

6.2.11 Procedures

A. Study Entry

Required assessments will be completed as depicted in Tables 1 and 2.

-   -   Informed consent must be obtained by the principal investigator        or designee for all subjects prior to the initiation of any        study procedures. All subjects must review the sub-study portion        of the ICD (intensive PK, immunization and PG) prior to the        initiation of any study procedures and indicate whether or not        they consent to participate in this portion of the study.    -   Relevant medical history (including relevant GI symptoms,        neurological symptoms, alcohol and tobacco use, etc.)        information will be collected for each subject.    -   Information regarding prior/concomitant medication usage will be        collected for each subject. At the screening and baseline        visits, concomitant medications should be checked against the        list of prohibited medications to ensure required washout times        have been met. If a subject does not meet the medication washout        requirements, the study visit must be rescheduled.

B. Safety Assessment

On the days of study visits, subjects will take their IP dose at thesite.

Required assessments will be completed as depicted Tables 1 and 2.Assessments may be conducted at other times during the study if felt tobe clinically warranted by the Investigator.

-   -   Information regarding all AEs regardless of causal relationship        to IP (Compound 1A or placebo), occurring at any time for the        duration of the study, from the time of signing the ICD up to        and including the Observation Phase, will be collected.    -   Vital signs include temperature, pulse, and seated blood        pressure. Blood pressure will be measured after the subject has        been seated and resting quietly for 5 minutes.        -   On study visits where ECGs and PK evaluations are performed,            blood pressure measurements should be completed first.            Pre-dose ECGs should then be performed, followed by pre-dose            PK blood draws and IP dosing.    -   Complete physical examinations will include height (Screening        visit) and weight (Screening and the Final Treatment Visit—to be        done in street clothes, no shoes), skin, nasal cavities, eyes,        ears, respiratory, cardiovascular, gastrointestinal,        neurological, lymphatic, and musculoskeletal system evaluations.        Results of the physical examinations will be recorded only in        the source documents. Clinically significant abnormal findings        identified during the Screening physical examination will be        recorded on the e-CRF as medical history; clinically significant        findings identified during the final treatment visit physical        examination will be recorded as adverse events. Gynecological        and urogential examinations will not be done unless for cause.    -   Targeted physical examinations will include evaluation of the        skin, respiratory, cardiovascular, lymphatic, and        musculoskeletal systems. Results of the physical examinations        will be recorded only in the source documents. Clinically        significant abnormal findings identified during the targeted        physical examinations will be recorded on the eCRF as adverse        events. Gynecological and urogenital examinations will not be        done unless for cause.    -   Standard 12-lead ECGs will be obtained at most study visits. In        cases where ECG and PK timepoints coincide, a ±15 minute window        will be allowed for assessment completion (ECG should always be        assessed first). All ECGs from Visit 2 onward should be        performed 5 minutes apart after the subject has been in the        supine position for 3 minutes.        -   At Screening: one ECG will be performed        -   At required treatment visits: 3 ECGs will be done pre-dose        -   In the Observational Follow-Up Phase: one ECG will be            performe    -   Stimulatory agents and/or medications, e.g., caffeine, energy        drinks, licorice, theophylline, etc, should be avoided prior to        ECG administration. The same ECG equipment will be used        throughout the study. All ECG recordings will be manually        over-read on an ongoing basis by a cardiologist at the core ECG        laboratory for QT measurement and QTc calculation using Bazett's        and Fridericia's formula.    -   Laboratory Assessments        -   Pregnancy testing (urine and/or serum) for all FCBP        -   Serum chemistry (including total protein, albumin, calcium,            phosphorus, glucose, uric acid, total bilirubin, alkaline            phosphatase, AST [SGOT], ALT [SGPT], lipase, sodium,            potassium, chloride, bicarbonate, blood urea nitrogen,            creatinine, lactate dehydrogenase, [LDH], magnesium)        -   Hematology (complete blood count with differential and            platelets, absolute white blood cell counts,            apolipoproteins, total cholesterol)        -   Lipid-soluble vitamins (A, D, E, K)        -   PT, INR and PTT        -   Urinalysis (microscopic and quantitative protein)        -   Tetanus toxoid, meningococcal, pneumococcal and influenza            titers        -   Inflammation panel (including erythrocyte sedimentation rate            [ESR], fibrinogen, high sensitivity C-reactive protein            [hs-CRP], serum amyloid A)        -   Hepatitis screen (includes testing for Hepatitis B surface            antigen and antibody, Hepatitis B core antibodies (IgG/IgM)            and antibodies to Hepatitis C)        -   Quantitative assessment of immunoglobulins [immunoglobulin A            (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG)]        -   Lupus Anti-Phospholipid Profile (lupus anticoagulant,            anti-cardiolipin antibodies, antibodies to            beta-2-glycoprotein I and phosphatidylserine)            Detailed instructions for sample collection, processing,            storage, shipping and handling will be provided to the sites            in a separate manual.    -   Ophthalmological examinations will be conducted by a qualified        ophthalmologist. Testing will include visual acuity and slit        lamp exams with fluorescein staining following pupillary        dilation, focusing on the anterior chamber, iris and anterior        vitreous (unless use of fluorescein is contraindicated, eg due        to hypersensitivity).

Celgene Pregnancy Prevention Counseling Program (CPPCP).

C. Efficacy Assessments

In the event that a subject has taken systemic analgesics within 12hours of a study visit and/or systemic anti-pruritics within 48 hours ofa visit, their visit should be rescheduled. Health assessmentquestionnaires must be completed prior to any other study activities sothat responses most accurately reflect subjects' experiences before thestudy visit. If the subject needs help in completing the questionnaires,assistance should only be provided by study staff and not by familymembers. CLASI, DAS28, Hybrid SELENA SLEDAI and PGA assessments shouldbe conducted by the same trained Investigator or sub-investigatorthroughout the study.

CLASI Activity Score Assessment

The CLASI Activity Score ranges from 0 to 70. To generate the activityscore erythema is scored on a scale of 0 (absent) to 3 (dark red;purple/violaceous/crusted/hemorrhagic) and scale/hypertrophy are scoredon a scale of 0 (absent) to 2 (verrucous/hypertrophic). Both theerythema and scale/hypertrophy scores are assessed in 13 differentanatomical locations. In addition, the presence of mucous membranelesions is scored on a scale of 0 (absent) to 1 (lesion or ulceration),the occurrence of recent hair loss is captured (1=yes; 0=no) and non-scarring alopecia is scored on a scale of 0 (absent) to 3 (focal orpatchy in more than one quadrant). To calculate the activity score, allscores for erythema, scale/hypertrophy, mucous membrane lesions andalopecia are added together.

CLASI Damage Score Assessment

The CLASI Damage Score ranges from 0 to 56. To generate the damagescore, dyspigmentation is scored on a scale of 0 (absent) to 1(dyspigmentation) and scarring/atrophy/panniculitis are scored on ascale of 0 (absent) to 2 (severely atrophic scarring or panniculitis).Both the dyspigmentation and scarring/atrophy/panniculitis scores areassessed as usually lasting greater than or less than 12 months for thesubject. If the dyspigmentation usually lasts greater than 12 months,the dyspigmentation scoring conducted for the 13 anatomical areas isdoubled. In addition, scarring of the scalp (judged clinically), isscored on a scale of 0 (absent) to 6 (affects the whole skull). Tocalculate the damage score, all scores for dyspigmentation,scarring/atrophy/panniculitis, and scarring of the scalp are addedtogether.

Physician Global Assessment (PGA)

The PGA uses a visual analog scale with scores between 0 and 3 toindicate worsening of disease. The scoring is as follows:

-   -   0=none    -   1=mild disease    -   2=moderate disease    -   3=severe disease        This is a physician administered instrument used to gauge a        subject's overall state of health. A 10% increase (0.3 points)        is considered a clinically relevant worsening of disease.

Swollen and Tender Joint Count

Using this tool, joint tenderness and swelling will be noted as“present” or “absent,” with no quantitation of severity. In order tomaintain consistency throughout the study, the same evaluator shouldperform the joint assessments for a given subject at a study site ateach study visit.

Hybrid SELENA SLEDAI

The hybrid SELENA SLEDAI measures disease activity through assessment of24 lupus manifestations using a weighted score of 1 to 8 points. Adecrease of 4 or greater points in the Hybrid SELENA SLEDAI isconsidered clinically meaningful. A manifestation is recorded if it ispresent over the previous 10 days regardless of severity or whether ithas improved or worsened. What differentiates the hybrid SELENA SELEDAIfrom the SELENA SLEDAI is the definition of proteinuria. The HybridSELENA SLEDAI defines proteinuria as >0.5 gm/24 hours—new onset orrecent increase of more than 0.5 gm/24 hours' has been removed from thedefinition.

Pericarditis/Pleuritic Numerical Pain Scale

Each scale is scored using numerical values of 1 through 10-1representing ‘no pain’ and 10 representing ‘worst possible pain’. Bothpain scales will be self-administered by the subject and gauge theseverity of their SLE pain related to pericardial and pleuriticdiscomfort. Any indication from subjects or study assessments, asidefrom pain, which indicate clinically significant pericardial orpleuritic manifestations of SLE must be thoroughly investigated. Ifclinically significant SLE related complications are found, the subjectshould be discontinued from the study into the Observational Follow-UpPeriod and treated appropriately.

D. QoL Assessments

Required assessments will be completed as depicted in Tables 1 and 2.

SF-12

The SF-12 is a self-administered instrument consisting of 8 multi itemscales that assess 8 health domains: 1) limitations in physicalactivities because of health problems; 2) limitations in socialactivities because of physical or emotional problems; 3) limitations inusual role activities because of physical health problems; 4) bodilypain; 5) general mental health (psychological distress and well-being);6) limitations in usual role activities because of emotional problems;7) vitality (energy and fatigue); and 8) general health perceptions. Theconcepts measured by the SF-12 are not specific to any age, disease, ortreatment group, allowing comparison of relative burden of differentdiseases and the relative benefit of different treatments.

FACIT-F

The FACIT-Fatigue scale is a 13-item self-administered questionnairethat assesses both the physical and functional consequences of fatigue.Each question is answered on a 5-point scale, where 0 means “not atall,” and 4 means “very much.” Higher scores denote higher levels offatigue. It is expected that the FACIT-Fatigue score will decrease asimprovements are made in subjects' SLE.

EQ-5D

The EQ-5D measures the subject's general health state as a vertical VASand 6 quality of life domains as multiple choice questions: mobility,self-care, main activity (work, study, housework), family/leisureactivities, pain/discomfort, and anxiety/depression, the combination ofwhich generates 216 possible health states.

DLQI

DLQI will be assessed by the subject upon arrival at the site before anyother procedures or assessments are performed. The DLQI was developed asa simple, compact, and practical questionnaire for use in a dermatologyclinical setting to assess limitations related to the impact of skindisease. The instrument contains ten items dealing with the subject'sskin. With the exception of Item Number 7, the subject responds on afour-point scale, ranging from “Very Much” to “Not at All.” Item Number7 is a multi-part item, the first part of which ascertains whether thesubject's skin prevented them from working or studying (Yes or No), andif “No,” then the subject is asked how much of a problem the skin hasbeen at work or study over the past week, with response alternativesbeing “A lot,” “A little,” or “Not at all.” The DLQI Total score has apossible range of 0 to 30, with 30 corresponding to the worst quality oflife, and 0 corresponding to the best score. The developers suggest thatthe DLQI can be grouped into six subscales: symptoms and feelings; dailyactivities; leisure; work/school; personal relationships; and treatment.Scores for four of the subscales (symptoms and feelings, dailyactivities, leisure, and personal relationships) range from 0 to 6;scores for two of the subscales (work/school and treatment) range from 0to 3. Higher scores correspond to poorer quality of life.

LupusPRO

The LupusPRO is a disease targeted patient reported outcome tool forpatients with SLE. It was developed from ethnically diverse US patientswith SLE. It has been validated for use in the US. It has 43 items ofwhich 30 items are for health related quality of life (Jolly, 2007;Jolly, 2008; Cervera, 2010).

Disability Index of the Health Assessment Questionnaire (HAQ-DI)

The HAQ-DI is a 20-question, self-administered instrument that measuresthe subject's functional ability on a 4-level difficulty scale (0 to 3,with 0 representing normal or no difficulty; and 3 representing aninability to perform). Eight categories of functioning are included:dressing, rising, eating, walking, hygiene, reach, grip, and usualactivities (Bruce et al., J. Rheumatol., 2003, 30:167-78). This scale issensitive to change and is a good predictor of future disability(Aletaha et al., Rheum. Dis. Clin. North Am., 2006, 32:9-44).

E. Other Assessments—Pharmacokinetics

All subjects will participate in sparse PK as a participant in the mainstudy. Completion of intensive pharmacokinetics requires the subject tohave consented using the sub-study informed consent form. Both intensiveand sparse PK samples will be collected to evaluate Compound 1A PK.Intensive PK samples may also be measured for the R-enantiomer. Dosingand sample collection information including Compound 1A dose level,dosing date, dosing time (24 hour clock), and actual PK blood samplingtime (24 hour clock) should be accurately documented on the appropriateeCRF pages.

Spare PK Sampling

All other subjects who do not participate in the intensive PK portion ofthe study will have sparse PK samples collected. Pharmacokinetic bloodsamples (approximately 12 mL total) will be collected in subjects(unless the site does not have PK capabilities) who do not participatein intensive PK sampling at the following time points: Days 15, 29, 57and 85: one pre-dose sample per visit.

Intensive PK Sampling

Participation in the intensive PK assessment will be an optionalsub-study for which a separate consent will be signed at screening.Frequent collection of PK blood samples (approximately 57 mL total) willbe performed in a minimum of 4 subjects per treatment group (a total of32 subjects at the minimum) at the following time points:

-   -   Visit 2 (Baseline—Day 1): predose (Time=0), 1, 2, 3, 4, between        6 and 8 hours and 24 hours (±5 hours) after administration of        IP.    -   Visit 4 (Day 15): one predose sample per visit    -   Visit 6 (Day 29): predose (Time=0), 1, 2, 3, 4, between 6 and 8        hours and 24 hours (±5 hours) after administration of IP.    -   Visits 8 and 10 (Days 57 and 85): one predose sample per visit

The IVRS will be used to ensure inclusion of a minimum of 4 intensive PKparticipants per dose group. Pharmacokinetic samples should be collectedwithin the following collection windows:

-   -   −30 to −5 minutes for the pre-dose sample    -   ±10 minutes for the samples collected at timepoints of 1-4 hours    -   ±20 minutes for the samples collected at the timepoint of        between 6 and 8 hours    -   ±5 hours for the sample collected at the timepoint of 24 hours        (this sample must be collected prior to the second dose)        At each time point, approximately 3 mL blood will be collected.        The concentration of Compound 1A in plasma will be determined.

On all PK visits, subjects must bring their IP to the study center andIP must be administered to subjects at the study center after thecollection of the predose PK blood sample. Subjects will be asked toreport the date and time of their last IP dose (prior to the currentstudy visit day) to the study staff during their visit at the studycenter. The IP dosing time on the day of the PK sample collection shouldalso be documented by the study staff.

In cases where ECG and PK time points coincide, a ±15 minute window willbe allowed for completion of PK (the ECG should always be assessedfirst).

F. Other Assessments—Pharmacodynamics

Peripheral Blood Biomarkers

PD blood biomarker measurements will be collected as follows:

-   -   Drug Target Engagement: Peripheral blood aiolos and ikaros by        flow cytometry at Day 1, Day 29, Day 57 and Day 85 in Part 1 and        Day 1 in Part 2    -   Immune System: Peripheral blood B cells, T cells, CD3+, CD4+,        CD8+, CD16+/56, CD 19+ lymphocyte subsets, and dendritic        cells (DC) by flow cytometry at Day 1, Day 29, Day 57 and Day 85    -   Disease Markers: Lupus Autoantibody/Complement Panel (anti-Ro,        anti-La anti-dsDNA, anti-smith, rheumatoid factor, anti-RNP, C3,        C4, CB-CAPs, CH50, ANA, ANCA, anti-thyroid antibodies) at Day 1,        8, 29 57 and Day 85 (or Early Termination), and Days 113, 141        (Part 1 only) and 169 (Part 1 only) of the Observational        Follow-up Phase

G. Other Assessments—Pharmacogenics

Participation in the PG assessment will be an optional sub-study forwhich a separate consent will be signed at screening. The attempt is toobtain as many subjects as reasonable. A single blood sample will beobtained at baseline for the genetic analysis to assess genetic markersassociated with Compound 1A efficacy or safety. Pharmacogenetic testingwill be conducted using DNA isolated from blood drawn at baseline. DNAwill be examined for the presence of polymorphisms in or near the genesassociated with SLE (including but not limited to the following genes:IKZF1 (gene encoding Ikaros), IKZF3 (gene encoding Aiolos), PRDM1 (geneencoding BLIMP-1), HLA-DRB1, BLK, BANK1, TNFAIP3, STAT4, IRF5, TNFSF4,TRIM27, OR2H2, MICB, CREBL1, HSD17B, JAZF1, ATGS, PTTG1, PXK, ITGAM,ETS1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1, IRF8, IL10, NCF2, IFIH1,TYK2, and the Compound 1A target-related genes CRBN (gene encodingcereblon) and CUL4A.

H. Other Assessments—Immunization

Participation in the Immunization sub-study will be optional for which aseparate consent will be signed at screening. The effect of Compound 1Aon immunizations in SLE subjects will be monitored by measuring tetanustoxoid, meningococcal and pneumococcal titers during the study. Subjectswho qualify (based upon their medical history) will have the opportunityto participate in an immunization sub-study where they will receivetetanus toxoid and meningococcal or pneumococcal immunizations at thestart of the treatment period.

Subjects who agree participate in the immunization sub-study mustqualify for each vaccination type according to the following set ofcriteria:

-   -   Tetanus Toxoid        -   Receipt of vaccine was less than 5 years prior to baseline        -   It is safe to provide to the subject per the investigator's            judgment    -   Meningococcal/pneumococcal        -   The subject can receive only the pneumococcal or the            meningococcal vaccine—not both. If the subject has not            received either vaccine within 5 years prior to the Baseline            Visit, only the pneumococcal vaccine should be given.            Subjects will only be eligible for the meningococcal vaccine            if they have received the pneumococcal vaccine within 5            years of the Baseline Visit and they have not received the            meningococcal vaccine within 5 years of the Baseline Visit.            If the subject has also received the meningococcal vaccine            within 5 years of the Baseline Visit they will not be            eligible to receive either vaccine.        -   It is safe to provide to the subject per the investigator's            judgment

6.3 Example 3 Overexpression of CRBN, IKZF1 and IKZF3 MRNA in SLE PBMC

Viably frozen PBMCs from healthy volunteers (N=10) or SLE patients(N=11) were obtained from Conversant Bio (Huntsville, Ala.). Cells werequickly thawed in 37° C., washed in PBS, pelleted with centrifugation,and immediately lysed in RLT buffer. Total RNA was purified with RNeasymini spin-column kits (Catalog # 74104) using QIAcube™ system (Qiagen,Valencia, Calif.). Purified RNA was reverse transcribed into cDNA usinga reverse-transcriptase kit (Applied Biosystems). Real-time quantitativeRT-PCR was performed using Taqman® PCR probes specific for CRBN (A),IKZF1 (B), and IKZF3 (C) in ViiA7 real time polymerase chain reaction(RT-PCR) system (Applied Biosystems) in duplicates. The quantity ofproduct was normalized to glyceraldehyde-3-phosphate dehydrogenase asthe endogenous housekeeping gene. Fold increase of gene expression wascalculated using comparative Ct method (2^(−ΔΔCt)). P values weregenerated using an unpaired t test.

Expression of Genes encoding Cereblon (CRBN), Ikaros (IKZF1), and Aiolos(IKZF3) in peripheral blood mononuclear cells from SLE patients comparedto normal controls is depicted in FIG. 2A, FIG. 2B, and FIG. 2C,respectively. The results demonstrate overexpression of CRBN, IKZF1 andIKZF3 mRNA in SLE PBMC. Compared to normal PBMC (N=10), SLE PBMC (N=11)expressed significantly higher levels of cereblon (CRBN), Ikaros(IKZF1), and Aiolos (IKZF3).

6.4 Example 4 Effects of Compound 1A on Aiolos and Ikaros Protein Levels

Human heparinized whole blood from normal healthy volunteers(Bioreclamation, Westbury, N.Y.) was treated with 0.1% DMSO and Compound1A (1, 10, 100 nM) for 18 hrs at 37° C., 5% CO₂. After 18 hrs, the bloodwas lysed and fixed with 1× Lyse/Fix Buffer (BD Biosciences) for 10minutes at 37° C. Washed cells with cold PBS and cells were firstmulticolor stained with mouse anti-human CD3-PE mAb, mouse anti-humanCD19-APC mAb and mouse anti-human-CD14-PerCP mAb (all from BDBiosciences) to identify CD3+ T cells, CD19+ B cells and CD14+monocytes, respectively. The cells were then permeabilized by adding BDPerm/Wash Buffer I. Blocked non-specific binding by added FcR BlockingReagent (Miltenyi Biotech) for 10 minutes prior to staining forintracellular Aiolos or Ikaros content. The cells were then stained withrabbit anti-human Aiolos polyclonal Ab (Santa Cruz, 1:200 dilution inPerm/Wash Buffer) or anti-human Ikaros polyclonal Ab (Santa Cruz, 1:50dilution in Perm/Wash Buffer), followed by a goat-anti-rabbit mAb-AF488Ab (Invitrogen, at 1:400 dilution in Perm/Wash Buffer) to test theintracellular Aiolos or Ikaros levels. Normal rabbit IgG (R&D Systems)was also used as isotype control. Aiolos and Ikaros protein levels in Bcells, T cells, monocytes and granulocytes were analyzed by FACSCantowith FACSDiva 6 (BD Biosciences) based on the gating of CD3+ cells,CD19+ cells, CD14+ cells and granulocytes (FSC/SSC). Data analysis wasperformed using Flowjo (Tree Star) software.

The results demonstrate that Compound 1A reduced Aiolos and Ikarosprotein levels in whole blood leukocyte subsets including CD19+ B cells(FIG. 3A), CD3+ T cells (FIG. 3B), CD14+ monocytes (FIG. 3C), andgranulocytes (FIG. 3D).

PBMCs were purified from human buffy coats using Ficoll-Paque method.CD19+ B cells were isolated from PBMC by following EasySep Human B cellenrichment cocktail protocol (StemCell Technologies Catalog # 19054).Fresh B cell cocktail was prepared by adding 50 μg/mL of humantransferrin to B cell medium (Iscove's medium with 10% PFBS, 1% P/S, and5 μg/mL human insulin). The required volume of medium needed for theexperiment was filtered through a 0.22 micron filter. B celldifferentiation cocktail (final concentration): recombinant humanInterleukin (IL)-2 (20 U/mL), IL-10 (50 ng/mL), IL-15 (10 ng/mL), CD40Ligand/TNFSFS/ histidine-tagged (50 ng/mL), polyHistidine mouse IgG1antibody (5 μg/mL), and ODN 2006-Human TLR9 ligand (10 μg/mL). CD19+cells were pretreated with Compound 1A or a Syk inhibitor or 0.1% DMSOfor 1 hr, then incubated with B-cell differentiation medium forindicated times.

Following incubation, cells were collected, pelleted withcentrifugation, and immediately lysed in 0.1 mL lysis buffer containing10 mM Tris-HCl pH 8.0, 10 mM EDTA, 150 mM NaCl, 1% NP-40, 0.5% SDS, 1 mMDTT, 1 mM Na3VO4, plus Complete™ protease inhibitor cocktail (RocheApplied Science, Indianapolis, Ind.), then processed with a QIAshredder™(Qiagen) for 1 minute and frozen on dry ice. Samples were diluted with6× SDS sample buffer and then boiled for 5 minutes. Approximately 15 μLof this mixture was loaded per lane on a Criterion Precast 10% Tris-HC1gel (Bio-Rad Laboratories, Hercules, Calif.), electrophoresed, andtransferred to nitrocellulose membranes (Bio-Rad). The membranes wereblocked for 1 hour at room temperature using blocking buffer (LI-CORBiosciences, Lincoln, Nebr.), then incubated overnight at 4° C. withantibodies against either Aiolos, Ikaros, or β-actin. Membranes werewashed and incubated with IRDye Secondary Antibodies (1:25,000) for 1hour at room temperature. A standard protocol was then followed forsignal detection and band quantification, using the Odyssey® InfraredImaging System and software (LI-COR Biosciences).

Effect of Compound 1A on Aiolos and Ikaros protein levels during CD19+ BCell Culture are depicted in FIG. 4A and FIG. 4B, respectively. Ikarosand Aiolos were measured by western blot.

Whole blood samples from patients identified with SLE were obtained fromSanguine Biosciences; Inc. the blood was diluted with sterile Dulbecco'sphosphate buffered saline solution (DPBS) and placed into three 50-mLconical tubes. Approximately 12 mL of Ficoll-Plaque was gentlyunder-layered in each tube and the tubes were centrifuged at 1000 g for35 minutes without brake. The interface containing mononuclear cells wascollected and transferred into two 50-mL conical tubes and the volume ineach conical tube was adjusted to 50 mL using DPBS. The mononuclearcells were washed with DPBS to remove Ficoll and platelets and afterthree washes the cell pellet was resuspended in 40 mL of B cell medium(Iscove's modified Dulbecco's medium +10% fetal bovine serum (FBS), 1%penicillin/streptomycin P/S, and 2 mM of L-Glutamine) to obtain aviability and cell count using trypan blue dye exclusion method. PBMCswere activated using the B cell differentiation cocktail described forFIG. 4A and FIG. 4B above. Cell culture supernatants were harvested andanalyzed for autoantibodies using an Anti-double stranded DNA antibodyELISA kit (Orgentec ORG 604S) and an Anti-Cardiolipin/Phospholipid ELISAkit (Orgentec ORG-529).

Compound 1A also inhibited SLE autoantibody production in vitro (FIG. 5Aand FIG. 5B). In cultures of SLE PBMC, Compound 1A inhibited productionof anti-dsDNA autoantibodies (N=9) and anti-phospholipid autoantibodies(N=8) with an IC50 of approximately 10 nM.

6.5 Example 5 Effects of Compound 1A in Healthy Volunteers

Healthy volunteers were administered placebo (n=10) or Compound 1A atdoses of 0.03 mg, 0.1 mg, 0.3 mg, 1 mg, or 2 mg (N=6 each). Bloodsamples were drawn prior to dosing, or 3 hr, 12 hr, and 24 hr afterdosing. Blood samples were lysed and fixed immediately by mixing 1volume of blood with 20 volumes of 1× Lyse/Fix buffer (BD Biosciences,cat# 558049) and mixing thoroughly by inverting the tube several times.This sample mix was incubated in a 37° C. water bath for 10 minutes.,and the cells were pelleted by centrifugation at 800×g for 5 minutes toremove the supernatant by aspiration. The cells were washed twice with 2mL of cold phosphate buffer saline (PBs), then permeabilized by adding 2mL of cold BD Cytofix/cytoperm buffer and incubated on ice for 15minutes. The cells were centrifuged than washed twice with BD perm/washbuffer, then resuspended in 40 ul of BD perm/wash buffer. Cells werestained with anti-CD3 or anti-CD19 antibody, and 20 ul of anti-Aiolos Ab(Santa Cruz Santa Cruz, rabbit polyclonal IgG, cat#sc-101982 at 1:200dilution with staining buffer), or 20 uL of appropriate isotype controlsto cells. Cells were mixed thoroughly and incubated at room temperaturefor 30 minutes in the dark, washed once with BD perm/wash buffer, thenresuspended in 80 ul of BD perm/wash buffer, and 20 uL of secondaryantibody was added before analysis on a flow cytometer.

The results demonstrate that Compound 1A reduced Aiolos expression in Bcells (FIG. 6A) and in T cells (FIG. 6B) at 0.3 mg, 1 mg, and 2 mgcohorts in healthy volunteers. FIG. 6A shows that, followingadministration of single doses of Compound 1A to healthy volunteers,there was a treatment-related decrease in B cell intracellular Aiolos.At 12 hours postdose, the 1- and 2-mg groups had percent of baselinevalues of 28.2% and 25.0%, respectively. At 24 hours postdose, the0.3-mg group had percent of baseline values of 24.8%. FIG. 6B showsthat, following administration of single doses of Compound 1A to healthyvolunteers, there was a treatment-related decrease in T cellintracellular Aiolos. At 12 hours postdose, the 1- and 2-mg groups hadpercent of baseline values of 22.3% and 26.1%, respectively; and at 24hours postdose, the 0.3-mg group had percent of baseline values of 0%.

Compound 1A also dose-dependently reduced peripheral blood B cell counts(FIG. 7A) in healthy volunteers. There was a dose-related decrease inthe maximum response in absolute CD19+ cells between 0.3 and 2 mgCompound 1A, with mean percent of baseline values of 73.5% on Day 3 for0.3 mg, 67.3% on Day 2 for 1 mg, and 51.3% on Day 3 for 2 mg. Absolute Bcell counts in the peripheral blood were measured by flow cytometry withanti-CD19 antibody as described above.

Compound 1A also reduced peripheral blood T cell counts (FIG. 7B) inhealthy volunteers. The results show that the T cell decrease is moremodest than B cell decrease. On Day 2, the 0.3-mg group had a percent ofbaseline value of 84.1% and the 1-mg group had 79.4%. On Day 5, the 2-mggroup had a percent of baseline value of 73.8%. Absolute T cell countsin the peripheral blood were measured by flow cytometry with anti-CD3antibody as described above.

Whole blood was stimulated with anti-CD3 antibody and analyzed for IL-2using the CD3 TruCulture system (Part number 782-001202) by Myriad RulesBased Medicine (Austin, Tex.). FIG. 8A shows that Compound 1A dosing inhealthy volunteers increased IL-2 production (pg/mL) inanti-CD3-stimulated whole blood ex vivo. There was a dose-relatedincrease in the maximum IL-2 in the 0.3-, 1-, and 2-mg groups, with meanpercent of baseline values of 315%, 973%, and 915%, respectively, at 12hours postdose on Day 1.

Whole blood was stimulated with lipopolysachharide and analyzed forIL-1β using the LPS TruCulture system (Part number 782-001087) by MyriadRules Based Medicine (Austin, Tex.). FIG. 8B shows that Compound 1Adose-dependently decreased ex vivo IL-1β production in healthyvolunteers at 0.3 mg, 1 mg, and 2 mg cohorts. For dose levels 0.3, 1,and 2 mg, there was a dose-related decrease in the maximum IL-1βresponse, with mean percent of baseline values of 42.2%, 21.8%, and16.3%, respectively, at 12 hours postdose.

What is claimed is:
 1. A method for treating or managing systemic lupuserythematosus (SLE), comprising administering to a patient in needthereof an effective amount of a compound of formula I

or a pharmaceutically acceptable salt, solid form, stereoisomer,tautomer or racemic mixture thereof, wherein the compound isadministered at an amount of from about 0.15 mg to about 0.6 mg per day.2. The method of claim 1, wherein the compound is(S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneor a pharmaceutically acceptable salt, solid form, or tautomer thereof.3. The method of claim 1, wherein the compound is(S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.4. The method of claim 1, wherein the compound is(S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride.
 5. The method of claim 1, wherein the SLE is skinpredominant SLE.
 6. A method for reducing or inhibiting a symptom ofsystemic lupus erythematosus (SLE), comprising administering to apatient having the symptom of systemic lupus erythematosus an effectiveamount of a compound, wherein the symptom is selected from the groupconsisting of joint pain, joint swelling, arthritis, chest pain whentaking a deep breath, fatigue, fever with no other cause, generaldiscomfort, uneasiness, hair loss, mouth sores, swollen lymph nodes,sensitivity to sunlight, skin rash, headaches, numbness, tingling,seizures, vision problems, personality changes, abdominal pain, nausea,vomiting, abnormal heart rhythms, coughing up blood and difficultybreathing, patchy skin color and Raynaud's phenomenon, and wherein thecompound is a compound of formula I

or a pharmaceutically acceptable salt, solid form, stereoisomer,tautomer or racemic mixture thereof, wherein the compound isadministered at an amount of from about 0.15 mg to about 0.6 mg per day.7. The method of claim 1, wherein the compound is administered at anamount of about 0.3 mg every other day (QOD).
 8. The method of claim 1,wherein the compound is administered at an amount of about 0.3 mg everyday (QD).
 9. The method of claim 1, wherein the compound is administeredat an amount of about 0.6 mg and about 0.3 mg on alternating days. 10.The method of claim 1, wherein the compound is administered at an amountof about 0.6 mg every day (QD).
 11. The method of claim 1, whereinadministration of the compound continues for a period of from about 2weeks to about 16 weeks.
 12. The method of claim 11, whereinadministration of the compound continues for a period of about 28 days.13. The method of claim 11, wherein administration of the compoundcontinues for a period of about 56 days.
 14. The method of claim 11,wherein administration of the compound continues for a period of about84 days.
 15. The method of claim 1, wherein the compound is administeredorally.
 16. The method of claim 15, wherein the compound is administeredin a capsule.
 17. The method of claim 16, wherein the capsule has anamount of about 0.3 mg of the compound.
 18. The method of claim 15,wherein the compound is administered in a tablet.
 19. The method ofclaim 1, wherein the SLE is severe SLE.
 20. The method of claim 1,wherein the patient has Cutaneous Lupus Area and Severity Index (CLASI)Activity Score ≥10.